EP0062902A1 - Dérivés 2,3,4-trinor-m-inter-phénylène-prostaglandine, leur préparation et compositions pharmaceutiques - Google Patents

Dérivés 2,3,4-trinor-m-inter-phénylène-prostaglandine, leur préparation et compositions pharmaceutiques Download PDF

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Publication number
EP0062902A1
EP0062902A1 EP82103024A EP82103024A EP0062902A1 EP 0062902 A1 EP0062902 A1 EP 0062902A1 EP 82103024 A EP82103024 A EP 82103024A EP 82103024 A EP82103024 A EP 82103024A EP 0062902 A1 EP0062902 A1 EP 0062902A1
Authority
EP
European Patent Office
Prior art keywords
inter
phenylene
pgi
trinor
general formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP82103024A
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German (de)
English (en)
Other versions
EP0062902B1 (fr
Inventor
István Dr. Székely
Krisztina Kékesi
Mariann Lovász geb. Gáspán
Sándor Botár
Pál Dr. Hadházy
István Dr. Rákoczi
László Dr. Muszbek
Judit Skopál
István Dr. Stadler
Károly Dr. Horváth
Gábor Dr. Kovács
Péter Dr. Körmöczy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chinoin Private Co Ltd
Original Assignee
Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Zrt
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from HU96381A external-priority patent/HU188286B/hu
Priority claimed from HU96481A external-priority patent/HU188009B/hu
Priority claimed from HU96281A external-priority patent/HU189974B/hu
Application filed by Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Zrt filed Critical Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Zrt
Publication of EP0062902A1 publication Critical patent/EP0062902A1/fr
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Publication of EP0062902B1 publication Critical patent/EP0062902B1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
    • C07D307/937—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans with hydrocarbon or substituted hydrocarbon radicals directly attached in position 2, e.g. prostacyclins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen

Definitions

  • the invention further relates to a process for the preparation of these compounds and the pharmaceutical preparations containing these compounds.
  • the compounds of the general formula are prostacyclin analogs with different pharmacological effects. They inhibit blood clotting, have a disaggregating effect on blood clots, have vasodilator, cytoprotective and ulcer healing effects.
  • Prostacyclin is an endogenous substance. It was discovered in 1976 by J.Vane et al. (Nature 1976, 263, 663; Prostaglandins 1976, 12, 685 and 897). The authors also found that PGI 2 plays a role in the hemostatic regulation of the circulatory system as an anti-aggregating and disaggregating agent.
  • prostacyclin The chemical synthesis of prostacyclin was achieved by several research groups (see eg Angewandte Chemie, International Edition 1978, 17, 293 and the references cited there).
  • the use of prostacyclin in medicine, for example to prevent infarction is severely limited by the exocyclic enol ether configuration in the prostacyclin structure and its instability.
  • Prostacyclin is a stable, readily storable compound in the form of its sodium salt, but under physiological conditions the PGI 2 acid 2 released from the sodium salt is rapidly hydrolyzed to 6-keto-PGF 1 £ , and this compound does not have the effect of PGI 2 .
  • All over the world, research into prostacyclin analogs is aimed at producing compounds that are more chemically stable and more selective in their action than PGI 2 .
  • the rigid structure of the molecule prevents the hydrolysis that occurs with prostacyclin and is catalyzed by its own carboxyl group.
  • the 2,3,4-trinor-m-inter-phenylene-PGI 2 derivatives of the general formula I can be prepared from the corresponding PGI 1 derivatives by elimination.
  • the elimination is triggered by bases.
  • bases Various reagents are possible as bases, for example alkali carbonates (potassium carbonate), alkali hydrogen carbonates (sodium hydrogen carbonate), alkali hydroxides (potassium hydroxide), but also tertiary amines, such as triethylamine, pyridine or 1,5-diazabicyclo [4,3,0] non-5 -en (DBN) or 1,5-diazabicyclo [5,4,0] undec-5-ene (DBU).
  • bases for example alkali carbonates (potassium carbonate), alkali hydrogen carbonates (sodium hydrogen carbonate), alkali hydroxides (potassium hydroxide), but also tertiary amines, such as triethylamine, pyridine or 1,5-diazabicy
  • the products obtained are purified by column chromatography on silica gel.
  • the C 1-4 alkyl group R 1 can be formed from the corresponding carboxylic acids, for example by reaction with diazoalkanes. If R 1 is an alkaline application or a primary, secondary, tertiary or quaternary ammonium ion, the preparation proceeds via the reaction of the corresponding acids and corresponding bases or amines. Products containing alkali ion instead of R 1 can also be obtained by hydrolysis the ester are made. Compounds in which Z represents a free amino group are prepared in such a way that the protective group previously introduced is cleaved off from the 16-amino group in the last stage.
  • Suitable protective groups are: C 1-4 -alkanoyl groups optionally substituted by halogen, alkoxycarbonyl, benzoyl, tosyl, benzyloxycarbonyl and p-nitrophenoxycarbonyl groups, which can be easily cleaved off in a manner known per se.
  • a C 1-4 alkyl group means the methyl, ethyl, n and isopropyl, n, iso, sec and tert-butyl group.
  • the C 1-4 -alkanoyl groups optionally substituted by halogen represent alkanoyl groups which can be derived from the corresponding alkanes and which can be mono- or polysubstituted by halogen. Examples of the substituents are: fluorine, chlorine, bromine and iodine.
  • the benzoyl group can be substituted by halogen or phenyl.
  • the alkyl groups can be the same or different. Examples of the C 4-6 alkyl groups are the straight and branched isomers of the butyl, pentyl, hexyl group.
  • the alkali ion R 1 can be a sodium, potassium or lithium ion.
  • Ammonium ions are to be understood as the linear or cyclic organic amines containing one or more nitrogen atoms, in which the nitrogen atom is substituted by one, two, three or four C 1-4 alkyl groups or by a C 5-8 cycloalkyl group, for example the cyclopentyl, Cyclohexyl, cycloheptyl or cyclooctyl group is substituted.
  • the alkyl groups bonded to the nitrogen atom can also be substituted, preferably by hydroxyl groups.
  • the most important pharmacological activity of the compounds of the invention is that, like PGI 2 , they inhibit platelet aggregation and have the property of dissolving agglomerates that have already formed.
  • the effect of the compounds of the invention on blood platelet rich plasma (PRP) from humans and guinea pigs was measured and compared with the effect of the known PGI 2 .
  • the measurement was carried out using the Born method.
  • the aggregation was triggered by ADP applied in a concentration of 4 ⁇ M / ml.
  • the prostacyclin concentration required for 50% and 100% inhibition was determined. The results are shown in the table below.
  • the compounds of the invention do not achieve the potency of the comparative compound, they are of great importance because their stability in aqueous medium exceeds the stability of the PGI 2 by orders of magnitude. To illustrate this, it should be noted that in aqueous pH 7 medium PGI 2 loses half of its activity within 3 minutes (ie, during this time half of the substance is decomposed), while the activity of the compounds of the invention only after 7 days has dropped to half.
  • the compounds of the invention can be formulated in a manner known per se with the extenders, fillers and excipients customary in the pharmaceutical industry to form pharmaceutical preparations. These can contain parts of the effective dose or an integer multiple thereof.
  • 250 mg (10.41 mM) sodium hydride are weighed into a well-dried three-necked flask equipped with a magnetic stirrer, thermometer and a rubber cap.
  • the flask is purged with nitrogen, then charged with 5 ml of dry dimethyl sulfide and connected to a nitrogen gas bottle.
  • a slow stream of nitrogen is passed through the flask, with a mercury seal in the line in the flask maintaining a weak N2 overpressure.
  • the temperature of the suspension is slowly increased to 60 ° C, a gas evolution being observed. After they have stopped (about 30 minutes), the mixture is heated to 70 ° C. and stirred at this temperature for a further 30 minutes.
  • a dark gray solution is obtained, to which 2.45 g (5.68 mM) of vacuum-dried m-carboxybenzyl-triphenyl-phosphonium chloride are added at 15 ° C.
  • the red solution obtained is stirred at room temperature for half an hour, then with the solution of 1.57 g (2.59 mM) 3.3 a, 4.5.6.6 a-hexahydro-2-hydroxy-4 ⁇ - (3- tetrahydropyranyloxy-4-phenoxy-butenyl) -5 ⁇ -tetrahydropyranyloxy-2H-cyclopenta [b] furan in 500 ml of anhydrous dimethyl sulfoxide, mixed at 60 ° C.
  • the solution is extracted twice with 10 ml of ether, the pH of the aqueous phase is adjusted to 4-5 with 2N aqueous sodium hydrogen sulfate solution, the aqueous phase is extracted 4 times with 20 ml of ether and then twice with 20 ml of ethyl acetate, and the is dried combined organic phases over sodium sulfate, filter and evaporate the solvent under reduced pressure.
  • the crude product obtained (2.5 g) is dissolved in 20 ml of ether and diazomethane solution is added dropwise at 0 ° C. while stirring until the yellow color of the added diazomethane no longer disappears.
  • the methyl ester formed is checked by layer chromatography.
  • the R f value of the acid formed in the Wittig reaction is 0.52 and that of the methyl ester prepared from it is 0.73. (If the formation of the methyl ester was not quantitative, further ethereal diazomethane solution is added ).
  • the aqueous phase is extracted 3 times with 50 ml of ether and then with 20 ml of ethyl acetate.
  • the combined organic phases are dried over natri sulfate, filter and then distill off the solvent under reduced pressure to give 530 mg of crude product.
  • the product is chromatographed on a column filled with 100 g of silica gel (Merck Art. No. 7734, particle size 0.03-0.2 mm) with ethyl acetate, the fractions on the analytical thin layer (Merck Art. No. 5715) containing the R f values 0.49 and 0.47 are combined.
  • the solvent is distilled off under reduced pressure.
  • the two product fractions together weigh 493 mg (87%).
  • the R f value of the endo or exoisomer measured by thin layer chromatography (silica gel G. Merck Art. No. 5715) with ethyl acetate is 0.49 and 0.47, respectively.
  • the crude 2,3,4-trinor-1,5-inter-m-phenylene-16- (trifluoroacetamido) -PGF 2 ⁇ -methyl ester obtained is dissolved in 5 ml of an anhydrous mixture of chloroform and tetrahydrofuran (ratio 1: 1) dissolved, the solution obtained cooled to -78 ° C (cold mixture of dry ice and acetone) and stirred under a protective gas atmosphere. After addition of 215.4 mg (1.21 mM) of solid N-bromosuccinimide, the reaction mixture is stirred at -78 ° C. for a further 10 minutes, then the cooling is stopped. The temperature of the reaction mixture is allowed to rise to room temperature and is stirred at this temperature for 30 minutes.
  • reaction mixture is diluted with 50 ml of chloroform and washed 3 times with 20 ml of water.
  • the tube product is chromatographed on a column filled with 60 g of silica gel (Merck Art.No. 7734, particle size 0.03-0.2 mm) with a mixture of ether and acetone (ratio 3: 1).
  • the fractions corresponding to the R f values 0.49 and 0.51 determined by thin-layer chromatography (Merck Art. No. 5715, eluent: ethyl acetate) are collected and the solvent is removed by distillation. A total of 152.1 mg (85.4%) of product are obtained.
  • R f 0.43 (benzene, dioxane and acetic acid 20: 10: 1) 1 NM R (deuteromethanol, ⁇ ): 5.32 (broad s, 1H, protons in 5-position), 5.45 - 5.77 (m, 2H, olefin protons), 6.9 - 7.5 (m, 6H, aromatic protons), 7.5 - 8.15 (m, 3H, aromatic protons).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP82103024A 1981-04-14 1982-04-08 Dérivés 2,3,4-trinor-m-inter-phénylène-prostaglandine, leur préparation et compositions pharmaceutiques Expired EP0062902B1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
HU96281 1981-04-14
HU96381A HU188286B (hu) 1981-04-14 1981-04-14 ELJÁRÁS 23,4-TRINOR-M-INTER-FENILIDÉN-PGl! SZÁRMAZÉKOK ELŐÁLLÍTÁSÁRA
HU96381 1981-04-14
HU96481A HU188009B (en) 1981-04-14 1981-04-14 Process for preparing new derivatives of 2,3,4-trinor-1,5-inter-m-phenylene-pgt down 2alpha
HU96281A HU189974B (hu) 1981-04-14 1981-04-14 Eljárás 2,3,4-trinor-m-iníer-fenilidén-PGI2 származékok előállítására
HU96481 1981-04-14

Publications (2)

Publication Number Publication Date
EP0062902A1 true EP0062902A1 (fr) 1982-10-20
EP0062902B1 EP0062902B1 (fr) 1986-01-15

Family

ID=27269950

Family Applications (1)

Application Number Title Priority Date Filing Date
EP82103024A Expired EP0062902B1 (fr) 1981-04-14 1982-04-08 Dérivés 2,3,4-trinor-m-inter-phénylène-prostaglandine, leur préparation et compositions pharmaceutiques

Country Status (12)

Country Link
US (1) US4451483A (fr)
EP (1) EP0062902B1 (fr)
AT (1) AT381494B (fr)
CS (1) CS241102B2 (fr)
DD (1) DD202434A5 (fr)
DE (1) DE3268487D1 (fr)
DK (1) DK165882A (fr)
FI (1) FI75156C (fr)
GR (1) GR76127B (fr)
IL (1) IL65387A0 (fr)
PL (1) PL129427B1 (fr)
SU (1) SU1138020A3 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0080718A1 (fr) * 1981-12-01 1983-06-08 CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. Dérivés inter-m-phénylène-PGI2, procédé pour leur préparation et compositions pharmaceutiques les contenant
DE3317159A1 (de) * 1982-05-27 1983-12-01 Grünenthal GmbH, 5190 Stolberg Verfahren zur herstellung von 5z-formen von 2,3,4-trinor-1,5-inter-m-phenylen- prostacyclinderivaten
US4479945A (en) * 1981-12-01 1984-10-30 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara R.T. Inter-m-phenylene-prostacyclin analogues and use thereof in inhibiting blood platelet aggregation
FR2553773A1 (fr) * 1983-09-19 1985-04-26 Squibb & Sons Inc Derives d'acides prostaglandine-phenylalcanoiques 7-oxabicyclo-substitues utiles notamment comme agents cardiovasculaires et medicaments les contenant
DE3408699A1 (de) * 1984-03-08 1985-09-12 Schering AG, 1000 Berlin und 4709 Bergkamen Neue carbacycline, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
AT381309B (de) * 1982-05-27 1986-09-25 Gruenenthal Gmbh Verfahren zur herstellung von 5z-formen von 2,3,4 -trinor-1,5-inter-m-phenylen-prostacyclinderiva en
US5661178A (en) * 1995-09-01 1997-08-26 Allergan Method for effecting vasodilation with (1,5-inter)aryl prostaglandin derivatives

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU190007B (en) * 1982-05-06 1986-08-28 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt,Hu Process for producing new aromatic prostacylin analogues

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2945781A1 (de) * 1978-11-22 1980-06-12 Upjohn Co Prostacyclinzwischenprodukte und protacyclinanaloge
EP0045842B1 (fr) * 1980-08-08 1984-01-18 Grünenthal GmbH Composés hétérocycliques, leur préparation et application comme thérapeutiques

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE795200A (fr) * 1972-05-10 1973-08-09 Ciba Geigy Nouveaux oxabicyclooctanes et leurs procedes de preparation
HU179001B (en) * 1978-05-29 1982-08-28 Chinoin Gyogyszer Es Vegyeszet Process for preparing 5-halo-6,9alpha-oxido-prostaglandin derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2945781A1 (de) * 1978-11-22 1980-06-12 Upjohn Co Prostacyclinzwischenprodukte und protacyclinanaloge
EP0045842B1 (fr) * 1980-08-08 1984-01-18 Grünenthal GmbH Composés hétérocycliques, leur préparation et application comme thérapeutiques

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0080718A1 (fr) * 1981-12-01 1983-06-08 CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. Dérivés inter-m-phénylène-PGI2, procédé pour leur préparation et compositions pharmaceutiques les contenant
US4479945A (en) * 1981-12-01 1984-10-30 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara R.T. Inter-m-phenylene-prostacyclin analogues and use thereof in inhibiting blood platelet aggregation
AT385271B (de) * 1981-12-01 1988-03-10 Chinoin Gyogyszer Es Vegyeszet Verfahren zur herstellung neuer inter-m-phenylen- prostacyclin-analoga
DE3317159A1 (de) * 1982-05-27 1983-12-01 Grünenthal GmbH, 5190 Stolberg Verfahren zur herstellung von 5z-formen von 2,3,4-trinor-1,5-inter-m-phenylen- prostacyclinderivaten
AT381309B (de) * 1982-05-27 1986-09-25 Gruenenthal Gmbh Verfahren zur herstellung von 5z-formen von 2,3,4 -trinor-1,5-inter-m-phenylen-prostacyclinderiva en
FR2553773A1 (fr) * 1983-09-19 1985-04-26 Squibb & Sons Inc Derives d'acides prostaglandine-phenylalcanoiques 7-oxabicyclo-substitues utiles notamment comme agents cardiovasculaires et medicaments les contenant
DE3408699A1 (de) * 1984-03-08 1985-09-12 Schering AG, 1000 Berlin und 4709 Bergkamen Neue carbacycline, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
US5661178A (en) * 1995-09-01 1997-08-26 Allergan Method for effecting vasodilation with (1,5-inter)aryl prostaglandin derivatives
US5750784A (en) * 1995-09-01 1998-05-12 Allergan Method for effecting vasodilation with (1,5-inter) aryl prostaglandin derivatives

Also Published As

Publication number Publication date
CS241102B2 (en) 1986-03-13
SU1138020A3 (ru) 1985-01-30
FI821164A0 (fi) 1982-04-02
EP0062902B1 (fr) 1986-01-15
ATA139282A (de) 1986-03-15
FI75156C (fi) 1988-05-09
DD202434A5 (de) 1983-09-14
US4451483A (en) 1984-05-29
AT381494B (de) 1986-10-27
GR76127B (fr) 1984-08-03
IL65387A0 (en) 1982-05-31
FI75156B (fi) 1988-01-29
DK165882A (da) 1982-10-15
PL129427B1 (en) 1984-05-31
FI821164L (fi) 1982-10-15
CS256182A2 (en) 1985-07-16
DE3268487D1 (en) 1986-02-27
PL235949A1 (en) 1983-01-03

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